Alzheimer's disease (AD), a progressive degenerative disease of the brain primarily associated with aging, is a serious healthcare problem. Clinically, AD is characterized by the of loss of memory, cognition, reasoning, judgment, and orientation. Also affected, as the disease progresses, are motor, sensory, and linguistic abilities until global impairment of multiple cognitive functions occurs. These cognitive losses take place gradually, but typically lead to severe impairment and eventual death in 4-12 years. Patients with AD display characteristic β-amyloid deposits in the brain and in cerebral blood vessels (β-amyloid angiopathy) as well as neurofibrillary tangles. Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of patients with Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and other neurodegenerative disorders. Neurofibrillary tangles also occur in other dementia-inducing disorders.
The family of proteins known as β-amyloid are thought to be causal for the pathology and subsequent cognitive decline in Alzheimer's disease. Proteolytic processing of the amyloid precursor protein (APP) generates amyloid β (A-beta) peptide; specifically, A-beta is produced by the cleavage of APP at the N-terminus by β-secretase and at the C-terminus by one or more γ-secretases. Aspartyl protease enzyme, or β-secretase enzyme (BACE), activity is correlated directly to the generation of A-beta peptide from APP (Sinha, et al, Nature, 1999, 402, 537-540). Increasingly, studies indicate that the inhibition of the β-secretase enzyme, inhibits the production of A-beta peptide. The inhibition of β-secretase and consequent lowering of A-beta peptide may lead to the reduction of β-amyloid deposits in the brain and β-amyloid levels in the cerebral blood vessels and to an effective treatment of a disease or disorder caused thereby.
Therefore, it is an object of this invention to provide compounds which are inhibitors of β-secretase and are useful as therapeutic agents in the treatment, prevention or amelioration of a disease or disorder characterized by elevated β-amyloid deposits or β-amyloid levels in a patient.
It is another object of this invention to provide therapeutic methods and pharmaceutical compositions useful for the treatment, prevention or amelioration of a disease or disorder characterized by elevated β-amyloid deposits or β-amyloid levels in a patient.
It is a feature of this invention that the compounds provided may also be useful to further study and elucidate the β-secretase enzyme.
These and other objects and features of the invention will become more apparent by the detailed description set forth hereinbelow.